Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof

Abstract

Provided herein are embodiments relating to therapeutic applications of antibodies that modulate; e.g., inhibit the interaction of TIM-3 and LILRB2 antibodies. In some embodiments, the antibodies bind TIM-3. In some embodiments the antibodies bind LILRB2. Modulation of the interaction of TIM-3 and LILRB2 stimulates the release of pro-inflammatory cytokines; e.g., myeloid-associated pro-inflammatory cytokines.

1 : An antibody which inhibits the interaction of TIM-3 and LILRB2. 
     
     
         2 : The antibody of  claim 1  which inhibits the binding of TIM-3 to LILRB2. 
     
     
         3 : An antibody which specifically binds TIM-3, wherein binding of the antibody to TIM-3 inhibits the interaction of TIM-3 to LILRB2. 
     
     
         4 : The antibody of  claim 3 , wherein binding of the antibody to TIM-3 inhibits binding of TIM-3 to LILRB2. 
     
     
         5 : The antibody of  claim 3 , wherein the antibody competes with LILRB2 for binding to TIM-3. 
     
     
         6 : The antibody of  claim 1  or  3 , wherein the TIM-3 is human TIM-3. 
     
     
         7 : The antibody of  claim 1  or  3 , wherein the TIM-3 comprises the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:3. 
     
     
         8 : The antibody of  claim 1  or  3 , wherein the amino acid sequence of the TIM-3 is at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:3. 
     
     
         9 : The antibody of  claim 1  or  3 , wherein the LILRB2 is human LILRB2. 
     
     
         10 : The antibody of  claim 1  or  3 , wherein the LILRB2 comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:7. 
     
     
         11 : The antibody of  claim 1  or  3 , wherein the amino acid sequence of the LILRB2 is at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:7. 
     
     
         12 : An antibody which specifically binds LILRB2, wherein binding of the antibody to LILRB2 inhibits the interaction of LILRB2 to TIM-3. 
     
     
         13 - 14 . (canceled) 
     
     
         15 : The antibody of  claim 1  or  3 , wherein the antibody competes with antibody mAb13, mAb15, mAb17, mAb22, mAb48, mAb58 and/or mAb91 for binding human TIM-3. 
     
     
         16 : The antibody of  claim 1  or  3 , wherein the antibody stimulates the secretion of one or more myeloid-associated cytokines in an individual. 
     
     
         17 : The antibody of  claim 16 , wherein the myeloid associated cytokine one or more of IL-12, TNFα, IL-1β, GM-CSF or IL-6. 
     
     
         18 : The antibody of  claim 16 , wherein the antibody stimulates the secretion of one or more myeloid-associated cytokines in an individual to a greater extent than the stimulation of secretion of the cytokine by antibody F38-2E2. 
     
     
         19 : The antibody of  claim 1  or  3 , wherein the antibody suppresses the secretion of a myeloid-associated cytokine in an individual. 
     
     
         20 : The antibody of  claim 19 , wherein the myeloid associated cytokine is IL-10, CCL2, CCL3, CCL4 or CCL5. 
     
     
         21 : The antibody of  claim 19 , wherein the antibody suppresses the secretion of a myeloid-associated cytokine in an individual to a greater extent than the suppression of secretion of the cytokine by antibody F38-2E2. 
     
     
         22 : An antibody the binds TIM-3, wherein the antibody stimulates the secretion of one or more myeloid-associated cytokines in an individual. 
     
     
         23 .- 31 . (canceled) 
     
     
         32 : The antibody of  claim 1  or  3 , wherein the antibody is a monoclonal antibody. 
     
     
         33 : The antibody of  claim 1  or  3 , wherein the antibody is a chimeric antibody, a humanized antibody or a human antibody. 
     
     
         34 - 35 . (canceled) 
     
     
         36 : The antibody of  claim 1  or  3 , wherein the antibody is an antibody fragment selected from a Fab, Fab′, Fv, scFv or (Fab′)2 fragment. 
     
     
         37 : A pharmaceutical composition comprising the antibody of  claim 1  or  3  and a pharmaceutically acceptable carrier. 
     
     
         38 : A method of modulating the secretion of a myeloid-associated cytokine in an individual, comprising administering to the individual a therapeutically effective amount of the antibody of  claim 1  or  3 . 
     
     
         39 - 48 . (canceled) 
     
     
         49 : A method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of the antibody of  claim 1  or  3 . 
     
     
         50 . (canceled) 
     
     
         51 : An isolated nucleic acid encoding the antibody of  claim 1  or  3 . 
     
     
         52 . (canceled) 
     
     
         53 : A host cell comprising the nucleic acid of  claim 51 . 
     
     
         54 : A host cell that produces the antibody of  claim 1  or  3 . 
     
     
         55 : A method for making an antibody that inhibits the interaction of TIM-3 and LILRB2, the method comprising culturing the host cell of  claim 54  under conditions suitable for expression of the nucleic acid encoding the antibody that inhibits the interaction of TIM-3 and LILRB2. 
     
     
         56 : An isolated nucleic acid encoding the antibody of  claim 22 . 
     
     
         57 - 58 . (canceled) 
     
     
         59 : A host cell that produces the antibody of  claim 22 . 
     
     
         60 : A method for making an antibody that binds TIM-3 and stimulates secretion of one or more myeloid-associated cytokines, the method comprising culturing the host cell of  claim 59  under conditions suitable for expression of the nucleic acid encoding the antibody. 
     
     
         61 - 73 . (canceled) 
     
     
         74 : A pharmaceutical composition for treating cancer in an individual comprising a therapeutically effective amount of an antibody that inhibits the interaction of TIM-3 and LILRB2 of  claim 1  or  3  and a pharmaceutically acceptable carrier. 
     
     
         75 : A kit for modulating of a myeloid-associated cytokine in an individual, comprising the antibody of  claim 1  or  3 . 
     
     
         76 - 84 . (canceled) 
     
     
         85 : A method for screening an agent which inhibits the interaction of TIM-3 and LILRB2, the method comprising measuring the binding of TIM-3 and LILRB2 in the presence of a candidate agent, wherein a reduction in the binding of TIM-3 and LILRB2 in the presence of the candidate agent by at least about 10% compared to binding of TIM-3 and LILRB2 in the absence of the candidate agent indicates that the agent inhibits the interaction of TIM-3 and LILRB2. 
     
     
         86 - 88 . (canceled) 
     
     
         89 : An antibody which specifically binds an epitope of TIM-3, wherein the epitope comprises the C′C″ and/or DE loop of TIM-3. 
     
     
         90 - 91 . (canceled) 
     
     
         92 : An antibody which specifically binds an epitope of TIM-3, wherein the epitope comprises the C′C″ loop of TIM-3. 
     
     
         93 - 95 . (canceled) 
     
     
         96 : An antibody which specifically binds an epitope of TIM-3, wherein the epitope comprises the DE loop of TIM-3. 
     
     
         97 - 114 . (canceled) 
     
     
         115 : A pharmaceutical composition comprising the antibody of  claim 89  and a pharmaceutically acceptable carrier.